During the first four years of the PPG, we have developed a new anticancer combination using adenovirus to deliver the manganese-containing superoxide dismutase (MnSOD) cDNA plus the commonly used anticancer agent BCNU. We have found this to be a very effective antitumor combination that exhibits very little normal cell toxicity when given intratumorally. We believe this protocol works because AdMnSOD raises intracellular peroxide levels and BCNU inhibits peroxide removal. Peroxides are very toxic to cancer cells. In the proposal, we plan to determine if we can obtain even better therapies based on similar principles and to examine further the mechanism of action. Specifically, we will examine the anticancer effects of AdMnSOD given with several compounds besides BCNU. These compounds are all modulators of the glutathione system, which aids in peroxide removal. In addition, we will see if inhibition of the other major peroxide removal system (catalase) will also add to the antitumor effect. We will determine if the copper- and zinc- containing superoxide dismutase (CuZnSOD) is also effective when combined with BCNU. We will ascertain whether the antitumor combinations studied are working as proposed by measuring the levels of various antioxidant and antioxidant proteins modulated. Last, we will determine if superoxide generation via commonly used anticancer agents (ionizing radiation, photodynamic therapy, adriamycin and tumor necrosis factor) or nitric oxide generation will increase the cancer cell killing induced by AdMnSOD plus BCNU.